Myocardial inflammation can lead to lethal acute or chronic heart failure (HF)

Myocardial inflammation can lead to lethal acute or chronic heart failure (HF). the role T cells play in the heart, including its crucial role for host defense to computer virus and myocardial healing postischemia, and its pathogenic role in chronic ischemic and nonischemic HF. We discuss a variety of mechanisms that contribute to the inflammatory damage to the heart, as well as regulatory mechanisms that limit the magnitude of T-cell-mediated inflammation. We also spotlight areas in which further research is needed to understand the role T cells play in the heart and distinguish the findings reported in experimental animal models and how they may translate to clinical observations in the human heart. as well as increased surface expression of the T-cell activation markers (CD25 and CD69) compared with healthy controls (103), thus providing further evidence in humans that (R)-ADX-47273 T-cell alterations accompany HFrEF and cardiac remodeling. The relative proportion of T-cell subsets has also been examined in HFrEF patients and appears to shift toward a general proinflammatory T-cell activation state. For example, in patients specifically with dilated cardiomyopathy, most of whom had evidence of circulating autoantibodies, FACS sorting of circulating T cells identified reduced proportion of Tregs (85). Several other studies have made similar observations but in more general forms of HFrEF, in which Tregs again decreased (47, 65, 85, 86, 88) in HFrEF patients, compared with non-HF patients. Along the same lines, others reported that this relative proportion of Th17 (proinflammatory) T cells increased (47) in HFrEF. These combined data suggest a shift toward a proinflammatory T-cell state thata cannot be suppressed (R)-ADX-47273 by the reduced Treg levels present in HFrEF. In addition, investigations in HFrEF patients have also detected differential T-cell phenotypes and function. Tregs isolated from HFrEF patients had less suppressive activity when coincubated CD4+ effector T cells (85, 86). Furthermore, Treg from HFrEF patients displayed increased susceptibility to apoptosis (88) providing further mechanistic support for reduction of Treg inhibitory potency as a component of the HFrEF phenotype. In humans with HFrEF, T-cell steps correlate with quantitative parameters of LV remodeling and dysfunction, in addition to simply associating categorically with the presence or absence of HF. The relative proportion of circulating Treg negatively correlates with BNP (47, 88), nt-proBNP, LV chamber remodeling (65, 86), and C-reactive protein (65), indicating that the reduction of Treg-mediated immunosuppression may promote worsening of these parameters. Reduction in Treg proportion is also associated with reduced LV systolic function and survival (65). On the other hand, increased Th17-cell proportion also correlates with NT-proBNP, further supporting the association of increased T-cell axis activity with myocardial abnormalities. Taken together, these observed relations between human T-cell subsets and markers of myocardial dysfunction and remodeling provide more compelling evidence that T cells may directly affect cardiac structure and function. Direct T-cell migration into the failing LV in HFrEF patients has been less extensively studied, however. Biopsy specimens from hearts of patients with dilated cardiomyopathy from presumed viral myocarditis unexpectedly exhibited reduced presence of antigen presenting dendritic cells compared with control healthy specimens (71), directly implicating alterations in T-cell axis cell components within the heart. Mediastinal lymph nodes of (R)-ADX-47273 HFrEF patients Rabbit polyclonal to SGK.This gene encodes a serine/threonine protein kinase that is highly similar to the rat serum-and glucocorticoid-induced protein kinase (SGK). had decreased Tregs (88), further identifying abnormalities of T cells within cardiac-associated tissue. More recently, we identified increased CD3+ (R)-ADX-47273 T infiltration in LV specimens from end-stage nonischemic cardiomyopathy patients compared with nonfailing controls (61). CD3+ T cells isolated from patients with severe HFrEF demonstrated increased adhesion to activated ECs, supporting that T cells from HF patients are prone to be recruited (R)-ADX-47273 to the myocardial tissue. These data, combined with the aforementioned associative observations of Treg/effector T-cell imbalance and markers of myocardial dysfunction and remodeling in HFrEF patients, provide further evidence that T-cell recruitment to the heart may directly alter cardiac structure and function as a plausible mechanism contributing to HFrEF. HFpEF. Unlike HFrEF, HFpEF has only more recently been identified and accepted as a distinct clinical entity. As such, the potential dysregulation of T cells in this phenotype remain less well explored. However, understanding the functions of T cells in promoting this condition in humans has significant clinical relevance, since currently no effective medical treatments for HFpEF exist. Importantly, most of the main predisposing factors for HFpEF, including diabetes, adiposity, metabolic syndrome, hypertension, and aging represent proinflammatory phenotypes, with T-cell abnormalities having been implicated in the pathogenesis of a number of these risk factors (49, 57). In fact, the current prevailing model holds that chronic systemic inflammation from these conditions drives endothelial dysfunction and subsequent derangements in myocardial intracellular signaling, thus promoting HFpEF pathophysiology. As in HFrEF, the ratio of Th17/Treg cells increases in patients with HFpEF, compared with non-HF patients (47). Compared with hearts from patients with HFrEF or with asymptomatic LV hypertrophy,.